The major goal of this project is to discover genetic factors and biophysical mechanisms that cause congenital contractures (e.g., clubfoot) in Distal Arthrogryposis (DA) syndromes, the most common cause of heritable contractures. We have delineated 10 different DA syndromes (i.e., DA1-DA10) and discovered that mutations in any one of 9 genes that encode myosins or regulatory proteins (i.e., troponin complex, tropomyosins, myosin binding proteins) collectively explain ~50% of DA cases. Using a resource of ~340 families and nearly 600 cases with DA, we will in Aim 1 discover new genes for both well known and novel forms of DA. This will be accomplished using both conventional candidate gene and linkage approaches, and facilitated by mapping data that show we have defined several new DA loci. We will also use a novel strategy to find genes for rare, monogenic disorders that involves massively parallel resequencing of all protein coding sequences in the human genome (the exome). The proteins encoded by the genes we have, to date, found to underlie DA are perhaps both quantitatively and qualitatively the most important molecules in skeletal muscle as they bring about the production of force. Consistent with this observation, we have shown that individual myofibers from persons with mutations in MYH3, the most common cause of DA, exhibit both diminished force production and increased time to relaxation. Therefore, in Aim 2 we will explore the mechanism(s) by which dysfunction of the contractile apparatus of skeletal myofibers in persons with mutations in different DA genes cause congenital contractures. Discovery of the genetic variants influencing DA disorders will substantially expand our understanding of biology of congenital contractures and will facilitate accurate diagnosis and improved management of myopathies in general, a group of diseases that broadly affects children and adults in our country. Our findings may well provide insights for novel therapeutics to mitigate or prevent congenital contractures in the U.S. and globally.)